Small molecule activator of Nm23/NDPK as an inhibitor of metastasis
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Lee, Jae-Jin; Park, Jimin; Song, Soonwha; Lee, Eunsun; Choi, Jung-Eun; Suh, Ji-Wan; Seo, Eun Kyoung; Shin, Dong Hae; Lee, Kong-Joo] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Kim, Hwang Suk; Lee, Hongsoo; Lee, Hee-Yoon] Korea Adv Inst Sci & Technol, Dept Chem, Daejeon 34141, South Korea; [Lee, Ji-Sun; Lee, Ho-Young] Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea; [Lee, Ji-Sun; Lee, Ho-Young] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 08826, South Korea; [Shin, Sang Chul; Kim, Eunice EunKyeong] Korea Inst Sci & Technol, Biomed Res Inst, Seoul 02792, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 NATURE PUBLISHING GROUP
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000159854
- 본문언어 영어
- Published As http://dx.doi.org/10.1038/s41598-018-29101-6
초록/요약
Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl] cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.
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